First-Line Avastin Ups Survival in Advanced NSCLC

First-Line Avastin Ups Survival in Advanced NSCLC

ASCO  A randomized phase II/III trial in more than
800 patients with previously untreated advanced nonsquamous non-small-cell
lung cancer (NSCLC) has shown a clinically significant survival advantage for
the addition of the angiogenesis inhibitor bevacizumab (Avastin) to the
standard platinum-based chemotherapy regimen. Reporting the results of ECOG
E4599 in a plenary session at the 41st Annual Meeting of the American Society
of Clinical Oncology (abstract 4), lead investigator Alan B. Sandler, MD,
commented, "This is the first randomized trial in the past 10 years to show a
survival advantage in patients with untreated metastatic disease, and the
first trial with a targeted agent that has shown a survival advantage in
combination with chemotherapy."

Dr. Sandler, medical director of thoracic oncology,
Vanderbilt-Ingram Cancer Center, Nashville, and associate professor of
medicine, Vanderbilt University Medical Center, said that the addition of the
angiogenesis inhibitor to a regimen of paclitaxel and carboplatin extended
median survival beyond 1 year for the first time among patients with advanced
nonsquamous NSCLC.

The study enrolled 878 patients with untreated stage IIIb or
IV nonsquamous NSCLC; 14% had stage IIIb disease. Because data from an earlier
phase II study of bevacizumab suggested that squamous cell NSCLC may confer
increased risk for grade 5 hemoptysis, patients with a squamous histology were
excluded from the trial, Dr. Sandler said. Patients were randomly assigned to
receive either paclitaxel at 200 mg/m2
and carboplatin to AUC 6 on day 1 every 3 weeks (n = 444) or the same regimen
plus bevacizumab at 15 mg/kg on day 1 every 3 weeks (n = 434). All patients
received six cycles of therapy, and those randomized to the chemotherapy plus
bevacizumab arm were treated with bevacizumab until toxicity became intolerable
or their cancer progressed.

At a median follow-up of 9.4 months, median survival time
was 12.5 months for patients who received bevacizumab plus chemotherapy vs 10.2
months for patients who received standard chemotherapy alone (P =
.0075). Progression-free survival time was 6.4 months with bevacizumab vs 4.5
months without it
(P < .0001), and the overall response to therapy was 27% for those
receiving bevacizumab vs 10% for patients receiving chemotherapy alone (P
< .0001).

An intriguing finding in a subset analysis was that men
treated with bevacizumab/chemotherapy survived longer than women randomized to
this regimen, Dr. Sandler told ONI. "Although these data are not
mature," he said, "it is possible that women who went off the trial may have
been administered tyrosine kinase inhibitors as second-line or even third-line
therapy, which may have been responsible for this survival difference."

The investigators will continue to collect retrospective
data from the study correlating biomarkers such as VEGF, fibroblast growth
factor (FGF), and cell-adhesion molecules with survival and response outcomes,
he added.

Well-Tolerated Regimens

Patients tolerated both regimens well, Dr. Sandler reported,
with hemoptysis, an adverse event of significant concern in similar trials,
being seen in the current study in only 1.3% of patients (n = 5) receiving
chemotherapy/bevacizumab. No patients in the chemotherapy-alone group developed
hemoptysis. "Hemoptysis was not a major concern and was not clinically
significant in this trial," Dr. Sandler commented. "In all likelihood, this is
because we excluded patients with NSCLC who had a squamous histology."

Grade 4-5 neutropenia was noted in 16.4% of patients on
chemotherapy alone vs 24% whose treatment included bevacizumab. Grade 3-4
thrombosis/embolism was seen in 3% vs 3.8% of patients, respectively, and
hemorrhage was observed in 1.0% vs 4.1% of patients, respectively.

There were 11 treatment-related deaths in the study: 2 were
in the chemotherapy-alone arm, and 9 were in the arm that included bevacizumab,
with 5 of these 9 deaths occurring from hemoptysis. (No deaths from hemoptysis
occurred with chemotherapy alone.)

Given the significant clinical improvements seen in this study, Dr. Sandler
noted that the regimen is ECOG’s new treatment standard for this patient
population. "This paclitaxel/carboplatin doublet in combination with
bevacizumab will be the accepted standard of care for patients with nonsquamous
NSCLC and ultimately other platinum-based doublets in combination with
bevacizumab," he concluded.